Recentincreasesintheepidemicsofobesity,diabetes,andbotheatingandgastrointestinal(GI)disordersunderscore thefactthatadequatetreatmentshaveyettobedeveloped.AstheNIHBRAINinitiativeandotherprogramshave stressed,theunderlyingbrain?gutcircuitrymustbecharacterizedifclinicalinterventionsaretobedevelopedefficiently. Theoverallgoalofthecurrentresearchprogramistousestate?of?the?artneuroscienceprotocolstocharacterizethose brain?gutpathways.Whilethepresentprojecthasmadeimportantprogressdelineatingtheautonomicprojectionsto theoutersmoothmusclewalloftheesophagus,stomach,andintestines,characterizationsoftheelementsofvagaland otherautonomiccircuitrythatinnervatetheinnermucosalandsubmucosalliningsoftheintestineshaveyettobe accomplished.Thislackofinformationfortheinnerwalloftheintestinesisproblematic,sincethevagalsensory innervationofthemucosalliningoftheGItractisfundamentalforintegratingtheinformationandpatternsofnutrient fluxes,caloricdensities,paracrinesignaling,andmicrobiomedynamicsthatcollectivelycontrolingestion,digestion, absorption,andmetabolismofnutrients.IntwocomplementaryseriesofexperimentsorganizedastwoSpecificAims, thepresentrenewalrequestproposestogeneratecomprehensivefoundationaldescriptionsofthevagalsensory projectionstothemucosaandsubmucosaoftheintestines.SpecificAim1proposesasetofsixcumulativeexperiments tophenotype,determine3Darchitecturalmorphometry,maptopographically,andestablishthesurgicalapproachto therecentlydescribedvagalcryptendingsthatinnervatetheintestinalglands.SA1willalsocomparethemorphology ofthecryptendingsinmalesandfemalesandassessremodelingoftheendingsasafunctionofmaintenanceonan obesogenichighfatdiet.SpecificAim2proposesaparallelsetofexperimentschacterizingthephenotype,3D morphometry,maps,andvagalpathwaysofthevagalvillusarborsthatinnervatetheepithelialwallsofintestinalvilli.In sum,thepresentprojectwillprovidefundamentalobservationsonthesensoryelementsofthebrain?intestinesaxisthat areimmediatelyinvolvedinintegratingtheGIsignalscontrollingmetabolism.